Aging is an important problem associated with diseases that dominate health care in America. Atherosclerosis is a common age-associated disease that causes much of the morbidity and mortality of growing old. Aging and vascular dysfunction are related to chronic oxidative damage. Elevated levels of glucose may cause oxidative damage through glycoxidation, a process related to the production of reactive oxygen species by mitochondria. Uncoupling proteins, which uncouple respiration and oxidative phosphorylation in mitochondria, decrease the production of reactive oxygen species in cultured cells. Skeletal muscle expression of uncoupling protein-1 (UCP1) lowers glucose levels in mice. The experiments in this application will test the related hypotheses that decreasing glycoxidation (by lowering glucose levels through skeletal muscle respiratory uncoupling) prolongs life and decreases atherosclerosis in mice, and that decreasing the production of reactive oxygen species in the vasculature (through aortic expression of UCP1) decreases atherosclerosis in mice. The following specific aims will be pursued: l. To determine if average and maximum life span are prolonged in skeletal muscle UCP1 transgenic mice and if caloric restriction, known to prolong life in wildtype mice, affects longevity in these mice. 2. To determine if skeletal muscle expression of UCP1 will decrease vascular disease in apolipoprotein E (apoE)-deficient mice, a model for atherosclerosis. 3. To determine if inducible expression of UCP1 in the aorta will protect mice from diet-induced atherosclerosis. This project has the potential to prove the concept that respiratory uncoupling is a feasible therapy for aging and vascular disease.